Novel compounds

ABSTRACT

The invention relates to thiophene carboxamides of formula (I), wherein R 1 , R 2 , R 3 , A, n and X are as defined in the specification, processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in therapy.

FIELD OF THE INVENTION

[0001] The present invention relates to thiophene carboxamidederivatives, processes and intermediates used in their preparation,pharmaceutical compositions containing them and their use in therapy.

BACKGROUND OF THE INVENTION

[0002] The NF-κB (nuclear factor κB) family is composed of homo- andheterodimers of the Re1 family of transcription factors. A key role ofthese transcription factors is to induce and coordinate the expressionof a broad spectrum of pro-inflammatory genes including cytokines,chemokines, interferons, MHC proteins, growth factors and cell adhesionmolecules (for reviews see Verma et. al., Genes Dev. 9:2723-35, 1995;Siebenlist et. al., Ann. Rev. Cell. Biol. 10:405-455, 1994; Bauerle andHenkel, Ann. Rev. Immunol., 12:141-179, 1994; Barnes and Karin, NewEngl. J. Med., 336:1066-1071, 1997).

[0003] The most commonly found Re1 family dimer complex is composed ofp50 NFκB and p65 Re1A (Baeuerle and Baltimore, Cell 53:211-217, 1988;Baeuerle and Baltimore, Genes (Dev. 3:1689-1698, 1989). Under restingconditions NF-κB dimers are retained in the cytoplasm by a member of theIκB family of inhibitory proteins (Beg et. al., Genes Dev., 7:2064-2070,1993; Gilmore and Morin, Trends Genet. 9:427-433, 1993; Haskil et. al.,Cell 65:1281-1289, 1991). However, upon cell activation by a variety ofcytokines or other external stimuli, IκB proteins become phosphorylatedon two critical serine residues (Traenckner et. al., EMBO J., 14:2876,1995) and are then targeted for ubiquitination and proteosome-mediateddegradation (Chen, Z. J. et. al., Genes and Dev: 9:1586-1597, 1995;Scherer, D. C. et. al., Proc. Natl. Acad. Sci. USA 92:11259-11263,1996;Alkalay, I. et. al., Proc. Natl. Acad. Sci. USA 92:10599-10603, 1995).The released NF-κB is then able to translocate to the nucleus andactivate gene transcription (Beg et. al., Genes Dev., 6:1899

[0004] A wide range of external stimuli have been shown to be capable ofactivating NF-κB (Baeuerle, P. A., and Baichwal, V. R., Adv. Immunol.,65:111-136, 1997). Although the majority of NF-κB activators result inIκB phosphorylation, it is clear that multiple pathways lead to this keyevent. Receptor-mediated NF-κB activation relies upon specificinteractions between the receptor and adapter/signalling molecules (forexample, TRADD, RIP, TRAF, MyD88) and associated kinases (IRAK, NIK)(Song et. al., Proc. Natl. Acad. Sci. USA 94:9792-9796, 1997; Natoli et.al., JBC 272:26079-26082, 1997). Environmental stresses such as UV lightand γ-radiation appear to stimulate NF-κB via alternative, less defined,mechanisms.

[0005] Recent publications have partially elucidated the NF-κBactivation. This work has identified three key enzymes which regulatespecific IκB/NF-κB interactions: NF-κB inducing kinase (NIK) (Boldin et.al., Cell 85:803-815, 1996), IκB kinase-1 (IKK-1) (Didonato et. al.,Nature 388:548,1997; Regnier at al., Cell 90:373 1997) and IκB kinase-2(IKK-2) (Woronicz et. al., Science 278:866, 1997; Zandi et. al., Cell91:243, 1997).

[0006] NIK appears to represent a common mediator of NF-κB signallingcascades triggered by tumour necrosis factor and interleukin-1, and is apotent inducer of IκB phosphorylation. However NIK is unable tophosphorylate IκB directly.

[0007] IKK-1 and IKK-2 are thought to lie immediately downstream of NIKand are capable of directly phosphorylating all three IκB sub-types.IKK-1 and IKK-2 are 52% identical at the amino acid level but appear tohave similar substrate specificities; however, enzyme activities appearto be different: IKK-2 is several-fold more potent than IKK-1.Expression data, coupled with mutagenesis studies, suggest that IKK-1and IKK-2 are capable of forming homo- and heterodimers through theirC-terminal leucine zipper motifs, with the heterodimeric form beingpreferred (Mercurio et. al., Mol. Cell Biol., 19:1526, 1999; Zandi et.al., Science; 281:1360, 1998; Lee et. al, Proc. Natl. Acad. Sci. USA95:9319, 1998).

[0008] NIK, IKK-1 and IKK-2 are all serine/threonine kinases. Recentdata has shown that tyrosine kinases also play a role in regulating theactivation of NF-κB. A number of groups have shown that TNF-α inducedNF-κB activation can be regulated by protein tyrosine phosphatases(PTPs) and tyrosine kinases (Amer et. al., JBC 273:29417-29423, 1998; Huet. al., JBC 273:33561-33565, 1998; Kaekawa et. al., Biochem. J.337:179-184, 1999; Singh et. al., JBC 271 31049-31054, 1996). Themechanism of action of these enzymes appears to be in regulating thephosphorylation status of IκB. For example, PTP1B and an unidentifiedtyrosine kinase appear to directly control the phosphorylation of alysine residue (K42) on IκB-α, which in turn has a critical influence onthe accessibility of the adjacent serine residues as targets forphosphorylation by IKK.

[0009] Several groups have shown that IKK-1 and IKK-2 form part of a‘signalosome’ structure in association with additional proteinsincluding IKAP (Cohen et. al., Nature 395:292-296, 1998; Rothwarf et.al., Nature 395:297-300, 1998), MEKK-1, putative MAP kinase phosphatase(Lee et. al., Proc. Natl. Acad. Sci. USA 95:9319-9324, 1998), as well asNIK and IκB. Data is now emerging to suggest that although both IKK-1and IKK-2 associate with NIK, they are differentially activated, andtherefore might represent an important integration point for thespectrum of signals that activate NF-κB. Importantly, MEKK-1 (one of thecomponents of the putative signalosome and a target for UV light, LPSinduced signalling molecules and small GTPases) has been found toactivate IKK-2 but not IKK-1. Similarly, NIK phosphorylation of IKK-1results in a dramatic increase in IKK-1 activity but only a small effecton IKK-2 (for review, see Mercurio, F., and Manning, A. M., CurrentOpinion in Cell Biology, 11:226-232, 1999).

[0010] Inhibition of NF-κB activation is likely to be of broad utilityin the treatment of inflammatory disease.

[0011] There is accumulating evidence that NF-κB signalling plays asignificant role in the development of cancer and metastasis. Abnormalexpression of c-Re1, NF-κB2 or IκBα have been described in a number oftumour types and tumour cell lines, and there is now data to show thatconstitutive NF-κB signalling via IKK2 takes place in a wide range oftumour cell lines. This activity has been linked to various upstreamdefects in growth factor signalling such as the establishment ofautocrine loops, or the presence of oncogene products e.g. Ras, AKT,Her2, which are involved in the activation of the IKK complex.Constitutive NF-κB activity is believed to contribute to oncogenesisthrough activation of a range of anti-apoptotic genes e.g. A1/Bfi-1,IEX-1, XIAP, leading to the suppression of cell death pathways, andtranscriptional upregulation of cyclin D1 which promotes cell growth.Other data indicate that this pathway is also likely to be involved inthe regulation of cell adhesion and cell surface proteases. Thissuggests a possible additional role for NF-κB activity in thedevelopment of metastasis. Evidence confirming the involvement of NF-κBactivity in oncogenesis includes the inhibition of tumour cell growth invitro and in vivo on expression of a modified form of IκBα(super-repressor IκBα).

[0012] In addition to the constitutive NF-κB signalling observed in manytumour types, it has been reported that NF-κB is also activated inresponse to certain types of chemotherapy. Inhibition of NF-κBactivation through expression of the super-repressor form of IκBα inparallel with chemotherapy treatment has been shown to enhance theantitumour effect of the chemotherapy in xenograft models. NF-κBactivity is therefore also implicated in inducible chemoresistance.

DISCLOSURE OF THE INVENTION

[0013] According to the present invention, there is provided a compoundof formula (I)

[0014] in which:

[0015] R¹ represents NH₂ or R¹ represents a methyl group optionallysubstituted by one or more groups selected independently from C₁-C₄alkyl, C₃-C₆ cycloalkyl, halogen, hydroxyl, C₁-C₄ alkoxy, S(O)_(v)CH₃and NR⁴R⁵.

[0016] X represents O or S;

[0017] R² represents hydrogen, halogen, cyano, nitro, —NR⁶R⁷,—CONR⁶R⁷—COOR, —NR⁶ COR7, —S(O)_(m)R⁶, —SO₂NR⁶R⁷-NR⁶SO₂ R⁷, C₁-C₂ alkyl,trifluoromethyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, trifluoromethoxy, C₁-C₂alkoxy or C₁-C₂ alkanoyl;

[0018] A represents a fused bicyclic ring system wherein one ring is aphenyl ring or a 5- to 7-membered heteroaromatic ring containing one tothree heteroatoms selected independently is from O N and S; and theother ring is either a fused phenyl ring or a fused 5- to 7-memberedheteroaromatic ring containing one to three heteroatoms selectedindependently from O, N and S, or a fused 5- to 7-membered saturatedring optionally incorporating one to three heteroatoms selectedindependently from oxygen, nitrogen and sulphur; said fused bicyclicring system being optionally substituted by one or more substituentsselected independently from halogen, cyano, nitro, —NR⁸ COR⁹,—S(O)_(s)R⁸, —SO₂NR⁸R⁹, —NR⁸ SO₂R⁹ and C₁-C₆ alkyl;

[0019] n represents an integer 0, 1 or 2; and when n represents 2, eachR³ group may be selected independently;

[0020] R³ represents a group —W—Y—Z wherein:

[0021] W represents O, S(O)_(r), NR¹³, CH₂, —CH₂—O— or a bond;

[0022] Y represents a bond or Y represents a group—(CH₂)_(p)—X—(CH₂)_(q)— wherein p and q independently represent aninteger 0, 1 or 2; and X represents O, —CO— or CR¹⁴R¹⁵;

[0023] R¹⁴ and R¹⁵ independently represent H, CH₃ or F;

[0024] or R¹⁴ represents H or CH₃ and R¹⁵ represents hydroxyl or OCH₃;

[0025] or the group CR¹⁴R¹⁵ together represents a C₃-C₆ cycloalkyl ring;

[0026] Z represents:

[0027] (a) a phenyl ring or a 5- or 6-membered heteroaromatic ringcontaining one to three heteroatoms selected independently from O, N andS; said phenyl or heteroaromnatic ring being optionally substituted byone or more substituents selected independently from halogen, cyano,—NR¹⁶R¹⁷, —CONR¹⁶R¹⁷, —COOR¹⁶, —COR¹⁶—NR¹⁶ COR¹⁷, —S(O)_(u)R¹⁶,—SO₂NR¹⁶R¹⁷, —NR¹⁶SO₂R¹⁷, hydroxyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkyl and C₁-C₆ alkoxy; said alkyl or alkoxy group being optionallyfurther substituted by one or more groups selected from halogen, cyano,hydroxyl, C₁-C₄ alkoxy and NR¹⁸ R¹⁹; or

[0028] (b) a saturated 3- to 7-membered ring optionally incorporatingone or two heteroatoms selected independently from O, N and S, andoptionally incorporating a carbonyl group; said saturated ring beingoptionally substituted by one or more substituents selectedindependently from halogen, cyano, —NR¹⁶R¹⁷, —CONR¹⁶R¹⁷, —COOR¹⁶, —COR¹⁶—NR¹⁶ COR¹⁷, —S(O)_(u)R¹⁶, —SO₂NR¹⁶R¹⁷, —NR¹⁶ SO₂R¹⁷, hydroxyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl and C₁-C₆ alkoxy; said alkyl oralkoxy group being optionally further substituted by one or more groupsselected from halogen, cyano, hydroxyl, C₁-C₄ alkoxy and NR¹⁸R¹⁹; or

[0029] (c) Z represents hydroxyl, C₁-C₆ alkoxy, CF₃, CHF₂, CH₂F orNR²⁰R²¹ where R²⁰ and R²¹ are independently hydrogen or C₁-C₆ alkyloptionally substituted by C₁-C₄ alcoxy;

[0030] R⁴ and R⁵ independently represent H or C₁-C₄ alkyl, or the groupNR⁴R⁵ represents a 5- or 6-membered saturated azacyclic ring optionallycontaining a further O, S or NR²³ group; where R²³ is hydrogen or C₁-C₄alkyl;

[0031] R⁶ and R⁷ independently represent H or C₁-C₂ allyl;

[0032] R⁸ and R⁹ independently represent H or C₁-C₆ alkyl;

[0033] R¹³ represents H or C₁-C₄ alkyl;

[0034] R¹⁶ and R¹⁷ independently represent H or C₁-C₆ alkyl; or thegroup NR¹⁶R¹⁷ represents a 5- or 6-membered saturated azacyclic ringoptionally containing a further O, S or NR²⁴ group; where R²⁴ ishydrogen or C₁-C₆ alkyl;

[0035] R¹⁸ and R¹⁹ independently represent H or C₁-C₄ alkyl; or thegroup NR¹⁸R¹⁹ represents a 5- or 6-membered saturated azacyclic ringoptionally containing a further O, S or NR²⁵ group; where R²⁵ ishydrogen or C₁-C₄ alkyl;

[0036] m, r, s, u and v independently represent an integer 0, 1 or 2;

[0037] and pharmaceutically acceptable salts thereof.

[0038] Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of the compounds offormula (I) and mixtures thereof including racemates. Tautomers andmixtures thereof also form an aspect of the present invention.

[0039] In one embodiment, X represents oxygen.

[0040] In another embodiment, R¹ represents CH₃ or NH₂. In a moreparticular embodiment, R¹ represents NH₂.

[0041] The compounds of formula (I) and their pharmaceuticallyacceptable salts have the advantage that they are inhibitors of theenzyme IKK2.

[0042] The invention further provides a process for the preparation ofcompounds of formula (I) or a pharmaceutically acceptable salt,enantiomer or racemate thereof.

[0043] According to the invention there is also provided a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use as amedicament.

[0044] Another aspect of the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament, for the treatment or prophylaxis ofdiseases or conditions in which inhibition of IKK2 activity isbeneficial.

[0045] Another aspect of the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament, for the treatment or prophylaxis ofinflammatory disease.

[0046] According to the invention, there is also provided a method oftreating, or reducing the risk of, diseases or conditions in whichinhibition of IKK2 activity is beneficial which comprises administeringto a person suffering from or at risk of, said disease or condition, atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof.

[0047] There is also provided a method of treating, or reducing the riskof; inflammatory; disease in a person suffering from or at risk of, saiddisease, wherein the method comprises administering to the person atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

[0048] In particular embodiments, the fused bicyclic ring system Arepresents optionally substituted quinoline, indole, benzothiophene,benzofuran, tetrahydroisoquinoline, 1,3-benzodioxolane(methylenedioxyphenyl) and 1,4-benzodioxane (ethylenedioxyphenyl).

[0049] In one embodiment, the group R² in formula (I) represents H,halogen or C₁-C₂ alkyl. In another embodiment, the group R² represents Hor methyl. In yet another embodiment, the group R² in formula(I)represents H.

[0050] Particular compounds of the invention include those exemplifiedherein:

[0051]2-[(aminocarbonyl)amino]-5-(2-benzofuranyl)-3-thiophenecarboxamide;

[0052] 2-[(aminocarbonyl)amino]-5-(3-quinolinyl)-3-thiophenecarboxamide;

[0053] 2-[(aminocarbonyl)amino]-5-(8-quinolinyl)-3-thiophenecarboxamide;

[0054]2-[(aminocarbonyl)amino]-5-(2-benzothiophenyl)-3-thiophenecarboxamide;

[0055]2-[(aminocarbonyl)amino]-5-(3-benzothiophenyl)-3-thiophenecarboxamide;

[0056] 2-[(aminocarbonyl)amino]-5-(5-indolyl)-3-thiophenecarboxamide;

[0057]2-[(aminocarbonyl)amino]-4-methyl-5-(1,4-benzodioxan-6-yl)-3-thiophenecarboxamide;

[0058]2-[(aminocarbonyl)amino]-4-methyl-5-(3-indolyl)-3-thiophenecarboxamide;

[0059]2-[(aminocarbonyl)amino]-4-methyl-5-(1,3-benzodioxo-5-yl)-3-thiophenecarboxamide;

[0060]2-[(aminocarbonyl)amino]-5-(1H-indol-2-yl)thiophene-3-carboxamide;

[0061]3-[(aminocarbonyl)amino]-5-1-benzothien-3-yl)thiophene-2-carboxamide;

[0062]2-[(aminocarbonyl)amino]-5-(2-morpholin-4-ylmethylbenzo[b]thiophen-5-yl)thiophene-3-carboxamide;

[0063]2-[(aminocarbonyl)amino]-5-[4-(2-morpholin-4-ylethoxy)-1-benzothien-2-yl]-3-thiophenecarboxamide;

[0064]2-[(aminocarbonyl)amino]-5-{2-[4-methylphenylsulphonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}thiophene-3-carboxamide;

[0065]3-[(aminocarbonyl)amino]-5-(1-benzothien-2-yl)thiophene-2-carboxamide;

[0066] and pharmaceutically acceptable salts thereof.

[0067] Unless otherwise indicated, the term “C₁-C₆ alkyl” referred toherein denotes a straight or branched chain alkyl group having from 1 to6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl and t-butyl. The terms “C₁-C₂ alkyl” and“C₁-C₄ aLiyl” are to be interpreted analogously.

[0068] Unless otherwise indicated, the term “C₂-C₃ alkenyl” referred toherein denotes a straight or branched chain alkyl group having 2 or 3carbon atoms incorporating at least one carbon-carbon double bond.Examples of such groups include ethenyl and propenyl. The term “C₂-C₆alkenyl” is to be interpreted analogously.

[0069] Unless otherwise indicated, the term “C₂-C₃ alkynyl” referred toherein denotes a straight chain alkyl group having 2 or 3 carbon atomsincorporating one carbon-carbon triple bond. Examples of such groupsinclude ethynyl and propynyl. The term “C₂-C₆ alkynyl” is to beinterpreted analogously.

[0070] Unless otherwise indicated, the term “C₃-C₆ cycloalkyl” referredto herein denotes a saturated carbocyclic ring having from 3 to 6 carbonatoms. Examples of such groups include cyclopropyl, cyclopentyl andcyclohexyl.

[0071] Unless otherwise indicated, the term “C₁-C₄ alkoxy” referred toherein denotes a straight or branched chain alkoxy group having 1 to 4carbon atoms. Examples of such groups include methoxy, ethoxy andisopropoxy. The terms “C₁-C₂ alkoxy” and “C₁-C₆ alkoxy” are to beinterpreted analogously.

[0072] Unless otherwise indicated, the term “CC₁-C₂ alkanoyl” referredto herein denotes a formyl or acetyl group.

[0073] Unless otherwise indicated, the term “halogen” referred to hereindenotes fluoro, chloro, bromo and iodo.

[0074] Examples of a 5- to 7-membered heteroaromatic ring containing oneto three heteroatoms selected independently from O, N and S includefuran, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole,imidazole, pyrazole, triazole, pyridine, pyridazine, pyrimidine andpyrazine. The term “a 5- or 6-membered heteroaromatic ring containingone to three heteroatoms selected independently from O, N and S” is tobe interpreted is, analogously.

[0075] Examples of a saturated 5- to 7-membered ring optionallyincorporating one to three heteroatoms selected independently from O, Nand S include cyclopentyl, cyclohexyl, tetrahydrofuran, pyrrolidine,piperidine, piperazine and morpholine.

[0076] Examples of a fused bicyclic ring system wherein one ring is aphenyl ring or a 5- to 7-membered heteroaromatic ring containing one tothree heteroatoms selected independently from O, N and S; and the otherring is either a fused phenyl ring or a fused 5- to 7-memberedheteroaromatic ring containing one to three heteroatoms selectedindependently from O, N and S; or a fused 5- to 7-membered saturatedring optionally incorporating one to three heteroatoms selectedindependently from oxygen, nitrogen and sulphur include naphthyl,quinoline, isoquinoline, tetrahydroisoquinoline, indole, benzothiophene,benzofuran, benzimidazole, 1,3-benzodioxolane (methylenedioxyphenyl) and1,4-benzodioxane (ethylenedioxyphenyl).

[0077] Examples of a 5- or 6-membered saturated azacyclic ringoptionally containing a fer O, or NR group include pyrrolidine,piperidine, piperazine and morpholine.

[0078] Examples of a saturated 3- to 7-membered ring optionallyincorporating one or two heteroatoms selected independently from O, Nand S, and optionally incorporating a carbonyl group includecyclopropyl, cyclohexyl, pyrrolidine, piperidine, morpholine,tetrahydrofuran, piperidin-2-one and piperidine-4-one.

[0079] According to the invention there is also provided a process forthe preparation of a compound of formula (I) or a pharmaceuticallyacceptable salt, enantiomer or racemate thereof which comprises:

[0080] (a) reaction of a compound of formula (II):

[0081] wherein A, R², R³ and n are as defined in formula (I) with anisocyanate or an isothiocyanate or an acyl derivative, R¹—CO-L where Lis a leaving group; or

[0082] (b) reaction of compound of formula (III)

[0083] wherein R³ n and A are as defined in formula (I)

[0084] with a compound of formula (IV)

[0085] wherein X, R¹ and R² are as defined in formula (I) and LGrepresents a leaving group; or

[0086] (c) reaction of compound of formula (V)

[0087] wherein R³, n and A are as defined in formula (I) and LGrepresents a leaving group,

[0088] with a compound of formula (VI)

[0089] wherein X, R¹ and R² are as defined in formula (I);

[0090] and where necessary converting the resultant compound offormula(I), or another salt thereof, into a pharmaceutically acceptablesalt thereof, or converting the resultant compound of formula (I) into afurther compound of formula (I); and where desired converting theresultant compound of formula (I) into an optical isomer thereof.

[0091] In process (a), suitable isocyanate reagents includetrimethylsilylisocyanate, trimethylsilylisothiocyanate,chlorosulphonylisocyanate, trichloroacetylisocyanate and sodiumisocyanate. The reaction with trimethylsilylisocyanate ortrimethylsilylisothiocyanate can be carried out in a solvent such asdichloromethane/dimethylformamide at a suitable elevated temperature,for example, at the reflux temperature of the reaction mixture. Thereaction with chlorosulphonylisocyanate can be carried out in a solventsuch as toluene at ambient temperature. The reaction with sodiumisocyanate can be carried out in a suitable solvent system such asaqueous acetic acid at ambient temperature. Thetrichloroacetylisocyanate reaction can be carried out in a suitablesolvent system such as acetonitrile at ambient temperature, andsubsequently treating the mixture with ammonia to give compounds of thegeneral formula (I). Suitable acyl derivatives of formula R¹—CO—Linclude acyl halides, particularly acyl chlorides, and acid anhydrides.Reactions with such acyl derivatives are generally carried out atambient temperature in a suitable solvent such as pyridine, or in asolvent such as dichloromethane in the presence of a suitable base suchas triethylamine or pyridine. Compounds of formula (I) wherein Xrepresents O may subsequently be converted into corresponding compoundsof formula (I) wherein X represents S by reaction with, for example,Lawesson's reagent.

[0092] In processes (b) and (c), the compounds of formulae (III) and(IV) or of formulae (V) and (VI) are reacted together under catalysisprovided by a complex of a transition metal such as palladium or nickel.In compounds of formulae (III) and (VI), under appropriate conditions,“metal” can be a metal or semi-metal such as magnesium, zinc, copper,tin, silicon, zirconium, aluminium or boron. Suitable leaving groupsinclude iodo, bromo, chloro, triflate or phosphonate.

[0093] It will be appreciated by those skilled in the art that in theprocesses of the present invention certain functional groups such ashydroxyl or amino groups in the starting reagents or intermediatecompounds may need to be protected by protecting groups. Thus, thepreparation of the compounds of formula (I) may involve, at anappropriate stage, the addition and removal of one or more protectinggroups.

[0094] The protection and deprotection of functional groups is fullydescribed in ‘Protective Groups in Organic Chemistry’, edited by J. W.F. McOmie, Plenum Press (1973), and ‘Protective Groups in OrganicSynthesis’, 3rd edition, T. W. Greene & P. G. M. Wuts,Wiley-Interscience (1999).

[0095] The present invention includes compounds of formula (I) in theform of salts, in particular acid addition salts. Suitable salts includethose formed with both organic and inorganic acids. Such acid additionsalts will normally be pharmaceutically acceptable although salts ofnon-pharmaceutically acceptable acids may be of utility in thepreparation and purification of the compound in question. Thus,preferred salts include those formed from hydrochloric, hydrobromic,sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic,succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.

[0096] Salts of compounds of formula (I) may be formed by reacting thefree base, or a salt, enantiomer or racemate thereof with one or moreequivalents of the appropriate acid. The reaction may be carried out ina solvent or medium in which the salt is insoluble or in a solvent inwhich the salt is soluble, for example, water, dioxane, ethanol,tetrahydrofuran or diethyl ether, or a mixture of solvents, which may beremoved vacuo or by freeze drying. The reaction may also be ametathetical process or it may be carried out on an ion exchange resin.

[0097] Compounds of formula (II) can be prepared by standard chemistrydescribed in the literature [for example, J. Het. Chem. 36, 333 (1999)]or by reaction of compounds of formula (VII:

[0098] where A, R², R³ and n are as defined in formula (I), and Lrepresents a leaving group, with ammonia. Suitable groups L includehalogen, in particular chloro.

[0099] Compounds of formula (VII) where L is halo can be prepared fromthe corresponding compound of formula (VIII):

[0100] where A, R², R³ and n are as defined in formula (I), by treatingwith a halogenating agent such as thionyl chloride.

[0101] Compounds of formulae (II), (I), (V), (VI) and (VI) arecommercially available or can be prepared using standard chemistry asexemplified herein.

[0102] Certain novel intermediate compounds form a further aspect of theinvention.

[0103] The compounds of formula (I) have activity as pharmaceuticals, inparticular as IKK2 enzyme inhibitors, and may be used in the treatment(therapeutic or prophylactic) of conditions/diseases in human andnon-human animals in which inhibition of IKK2 is beneficial. Examples ofsuch conditions/diseases include inflammatory diseases or diseases withan inflammatory component. Particular diseases include inflammatoryarthritides including rheumatoid arthritis, osteoarthritis, spondylitis,Reiters syndrome, psoriatic arthritis, lupus and bone resorptivedisease; multiple sclerosis, inflammatory bowel disease includingCrohn's disease; asthma, chronic obstructive pulmonary disease,emphysema, rhinitis, myasthenia gravis, Graves' disease, allograftrejection, psoriasis, dermatitis, allergic disorders, immune complexdiseases, cachexia, ARDS, toxic shock, heart failure, myocardialinfarcts, atherosclerosis, reperfusion injury, AIDS, cancer anddisorders characterised by insulin resistance such as diabetes,hyperglycemia, hyperinsulinemia, dyslipidemia, obesity, polycysticovarian disease, hypertension, cardiovascular disease and Syndrome X.

[0104] The reported roles of NF-κB in both oncogenesis andchemoresistance suggest that inhibition of this pathway through the useof an IKK2 inhibitor, such as a small molecule IKK2 inhibitor, couldprovide a novel monotherapy for cancer and/or an important adjuvanttherapy for the treatment of chemoresistant tumours.

[0105] We are particularly interested in diseases selected from asthma,rheumatoid arthritis, psoriasis, inflammatory bowel disease includingCrohn's disease, multiple sclerosis, chronic obstructive pulmonarydisease, bone resorptive disease, osteoarthritis, diabetes/glycaemiccontrol and cancer.

[0106] Thus, the present invention provides a compound of formula (I),or a pharmaceutically acceptable salt thereof, as hereinbefore definedfor use in therapy.

[0107] In a further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt thereof;as hereinbefore defined in the manufacture of a medicament for use intherapy.

[0108] In a still further aspect, the present invention provides the useof a compound of formula (I), or a pharmaceutically acceptable saltthereof; as hereinbefore defined in the manufacture of a medicament forthe treatment of diseases or conditions in which modulation of the IKK2enzyme activity is beneficial.

[0109] In the context of the present specification, the term “therapy”also includes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

[0110] Prophylaxis is expected to be particularly relevant to thetreatment of persons who have suffered a previous episode of, or areotherwise considered to be at increased risk of, the disease orcondition in question. Persons at risk of developing a particulardisease or condition generally include those having a family history ofthe disease or condition, or those who have been identified by genetictesting or screening to be particularly susceptible to developing thedisease or condition.

[0111] The invention still further provides a method of treating an IKK2mediated disease which comprises administering to a patient atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof, as hereinbefore defined.

[0112] The invention also provides a method of treating an inflammatorydisease, especially asthma, rheumatoid arthritis or multiple sclerosis,in a patient suffering from, or at risk of, said disease, whichcomprises administering to the patient a therapeutically effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt thereof, as hereinbefore defined.

[0113] For the above-mentioned therapeutic uses the dosage administeredwill, of course, vary with the compound employed, the mode ofadministration, the treatment desired and the disorder indicated.

[0114] The compounds of formula (I) and pharmaceutically acceptablesalts thereof may be used on their own but will generally beadministered in the form of a pharmaceutical composition in which theformula (I) compound/salt (active ingredient) is in association with apharmaceutically acceptable adjuvant, diluent or carrier. Depending onthe mode of administration, the pharmaceutical composition willpreferably comprise from 0.05 to 99% w (percent by weight), morepreferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w,and even more preferably from 0.10 to 50% w, of active ingredient, allpercentages by weight being based on total composition.

[0115] The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt thereof, as hereinbefore defined, in association with apharmaceutically acceptable adjuvant, diluent or carrier.

[0116] The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I), or a pharmaceutically acceptable salt thereof,as hereinbefore defined, with a pharmaceutically acceptable adjuvant,diluent or carrier.

[0117] The pharmaceutical compositions may be administered topically(e.g. to the lung and/or airways or to the skin) in the form ofsolutions, suspensions, heptafluoroalkane aerosols and dry powderformulations; or systemically, e.g. by oral administration in the formof tablets, capsules, syrups, powders or granules, or by parenteraladministration in the form of solutions or suspensions, or bysubcutaneous administration or by rectal administration in the form ofsuppositories or transdermally. Conventional procedures for theselection and preparation of suitable pharmaceutical formulations aredescribed in, for example, “Pharmaceuticals—The Science of Dosage FormDesigns”, M. E. Aulton, Churchill Livingstone, 1988.

[0118] The invention is illustrated, but in no way limited, by thefollowing examples:

EXAMPLE 1

[0119]2-[(Aminocarbonyl)amino]-5-(2-benzofuranyl)-3-thiophenecarboxamide

[0120] a) 2-Amino-3-thiophenecarboxamide

[0121] The title compound was synthesised as follows using the methoddescribed in Bull.Soc.Chim.France 2804 (1974).

[0122] A suspension of 2,5-dihydroxy-1,4-dithiane (25 g) andcyanoacetamide (19.3 g) in ethanol (120 ml) was stirred and heated to50° C. Triethylamine (9.2 ml) was added over 15 minutes and the mixturewas stirred at 50° C. for a further 2 h. After cooling in ice, the solidwas filtered off and dried (21.4 g).

[0123] MS (ES) 143(4+H)⁺.

[0124] b) 2-[(Aminocarbonyl)amino]-3-thiophenecarboxamide

[0125] 2-Amino-3-thiophencarboxamide (0.44 g) was suspended inacetonitrile (25 ml) and trichloroacetylisocyanate (0.2 ml) addeddropwise with stirring over 10 minutes. Stirring was continued for afurther 3 h at room temperature and then a solution of ammonia inmethanol (10 ml of a 2M solution) was added and stirring was continuedfor a further 2 h. The solvent was evaporated and the residue treatedwith water. The resultant solid was filtered off and washed with morewater. Trituration with ether gave the title urea (0.2 g).

[0126] MS (ES) 186 (M+H)⁺.

[0127] c) 2-[(Aminocarbonyl)amino]-5-bromo-3-thiophenecarboxamide

[0128] 2-[(Aminocarbonyl)amino]-3-thiophenecarboxamide (1.0 g) wasdissolved in acetic acid (20 ml) and a solution of bromine (0.35 ml) inacetic acid (5 ml) was added over 5 minutes with rapid stirring. Themixture was stirred for 90 minutes and then added to water (50 ml). Theproduct was filtered off and washed with water and dried under vacuum(0.55 g).

[0129] MS (ES) 262/264 (M−H)⁻.

[0130]¹HNMR (DMSO-D6) 7.15 (m, 1H), 7.35 (m, 1H), 7.8 (s, 1H), 7.9 (m,1H), 10.63 (brs, 1H).

[0131] d)2-[(Aminocarbonyl)amino]-5-(2-benzofuranyl)-3-thiophenecarboxamide

[0132] A solution of2-[(aminocarbonyl)amino]-5-bromo-3-thiophenecarboxamide (0.26 g), sodiumcarbonate (0.23 g) and benzofuran-2-boronic acid (0.32 g) indimethoxyethane (60 ml) and water (2 ml) was, purged with argon for 10minutes.

[0133] Tetrakis(triphenylphosphine)palladium (0.2 g) was then added andthe mixture refluxed with stirring for 7 h. After cooling, the mixturewas screened and evaporated. The residue was partitioned between ethylacetate and 3N sodium carbonate solution and the solid interface layerwas filtered off (0.2 g).

[0134] MS (ES) 300 (M−H).

[0135]¹H NMR (DMSO-D6) 6.9 (s, 1H), 7.05 (m, 2H), 7.2 (m, 2H), 7.3 (m,1H), 7.6 (m, 3H), 7.8 (m, 2H), 11.15 (brs, 1H).

EXAMPLE 2

[0136] 2-[(Aminocarbonyl)amino]-5-(3-quinolinyl)-3-thiophenecarboxamide

[0137] Prepared by the method of Example 1 (d) but usingquinoline-3-boronic acid.

[0138] MS (ES) 311 (M−H)⁻.

[0139]¹H NMR (DMSO-D6) 7.0, (m, 2H), 7.4 (m, 1H), 7.6 (m, 2H), 7.65 (m,2H), 8.0 (m, 2H), 8.4 (s, 1H), 9.15 (s, 1H), 11.06 (brs, 1H).

EXAMPLE 3

[0140] 2-[(Aminocarbonyl)amino]-5-(8-quinolinyl)-3-thiophenecarboxamide

[0141] Prepared by the method of Example 1 (d) but usingquinoline-8-boronic acid

[0142] MS (ES) 311 (M−H)⁻.

[0143]¹H NMR (DMSO-D6) 6.9 (m, 2H), 7.2 (m, 1H), 7.6 (m, 2H), 7.7 (m,1H), 7.8 (d, 1H), 8.1 (m, 2H), 8.4 (d, 1H), 9.0 (m, 1H), 11.01 (brs,1H).

EXAMPLE 4

[0144]2-[(Aminocarbonyl)amino]-5-(2-benzothiophenyl)-3-thiophenecarboxamide

[0145] Prepared by the method of Example 1 (d) but usingbenzothiophene-2-boronic acid.

[0146] MS (ES) 316 (M−H)⁻.

[0147]¹H NMR (DMSO-D6) 7.0 (m, 2H), 7.35 (m, 3H), 7.4 (s, 1H), 7.6 (s,1H), 7.8 (d, 1H), 7.85 (1,1H), 7.9 (d, 1H), 11.09 (s, 1H).

EXAMPLE 5

[0148]2-[(Aminocarbonyl)amino]-5-(3-benzothiophenyl)-3-thiophenecarboxamide

[0149] Prepared by the method of Example 1 (d) but usingbenzothiophene-3-boronic acid.

[0150] MS (ES) 316 (M−H)⁻.

[0151]¹H NMR (DMSO-D6) 6.95 (m, 2H), 7.25 (m, 1H), 7.4 (m, 2H), 7.65 (s,1H), 7.7 (s, 1H), 7.8 (m, 1H), 8.0 (d, 1H), 8.2 (d, 1H), 11.08 (brs,1H).

EXAMPLE 6

[0152] 2-[(Aminocarbonyl)amino]-5-(5-indolyl)-3-thiophenecarboxamide

[0153] Prepared by the method of Example 1 (d) but usingindole-5-boronic acid.

[0154] MS (ES) 299 (M−H)⁻.

[0155]¹H NMR (DMSO-D6) 6.4 (s, 1H), 6.8 (m, 2H), 7.2 (m, 1H), 7.3 (m,3H), 7.6 (s, 1H), 7.65 (m, 1H), 7.7 (s, 1H), 10.91 (s, 1H), 11.0 (brs,1H).

EXAMPLE 7

[0156]2-[(Aminocarbonyl)amino]-4-methyl-5-(1-benzodioxan-6-yl)-3-thiophenecarboxamide

[0157] a) 2-Amino4-methyl-5-(1,4-benzodioxan-6-yl)-3-thiophencarboxamide

[0158] 1,4-Benzodioxan-6-yl acetone (1.7 g), cyanoacetamide (0.84 g),sulphur (0.36 g) and morpholine (1 ml) in ethanol (5 ml) were stirredand heated at 55° C. for 6 h. The reaction mixture was cooled andscreened from a little insoluble before adding to water (150 ml). Theprecipitated solid was filtered off, washed with water and then dried.The product was then triturated with ether and collected (1.0 g).

[0159] MS (EI) 266 (M)⁺.

[0160]¹H NMR (DMSO-D6) 7.4 (2H, d), 7.3 (2H, d), 6.9 (2H, s), 6.8 (2H,s), 2.2 (33H, s).

[0161] b)2-[(Aminocarbonyl)amino]-4-methyl-5-(1,4-benzodioxan-6-yl)-3-thiophenecarboxamide

[0162] 2-Amino-4-methyl-5-(1,4-benzodioxan-6-yl)-3-thiophencarboxamide(0.44 g) was dissolved in tetrahydrofuran (10 ml), cooled to 0° C. andtrichloroacetylisocyanate (0.11 ml) added dropwise with stirring.Stirring was continued for a further 30 minutes at room temperature andthen a solution of ammonia in methanol (8 ml of a 10% solution) wasadded and stirring was continued for a further 3 h. The solvent wasevaporated and the residue treated with ethyl acetate and the productfiltered off.

[0163] MS (ES) 332 (M−H)⁻.

[0164]¹H NMR (DMSO-D6) 2.2 (s, 3H), 4.25 (s, 4H), 6.7 (m, 2H), 6.8 (m,2H), 6.9 (m, 1H), 7.2 (br, 1H), 10.01 (brs, 1H).

EXAMPLE 8

[0165]2-[(Aminocarbonyl)amino]-4-methyl-5-(3-indolyl)-3-thiophenecarboxamide

[0166] Prepared by the method of Example 7 but using indol-3-acetone.

[0167] MS (ES) 313 (M−H)⁻.

[0168]¹HNMR (DMSO-D6) 2.2 (s, 3H), 6.65 (brs, 2H), 7.05 (m, 1H), 7.1 (m,1H), 7.2 (m, 2H), 7.4 (m, 1H), 7.45 (d, 1H), 7.55 (d, 1H), 10.14 (brs,1H), 11.3 (m, 1H).

EXAMPLE 9

[0169]2-[(Aminocarbonyl)amino]-4-methyl-5-(1,3-benzodioxolan-5-yl)-3-thiophenecarboxamide

[0170] Prepared by the method of Example 7 but using1,3-benzodioxolan-5-acetone.

[0171] MS (ES) 318 (M−H)⁻.

[0172]¹H NMR (DMSO-D6) 2.2 (s, 3H), 6.05 (s, 2H), 6.8 (m, 1H), 6.9 (m,1H), 6.95 (m, 1H), 7.1 (m, 2H), 7.2 (m, 2H).

EXAMPLE 10

[0173] 2-[(Aminocarbonyl)amino]-5-(1H-indol-2-yl)thiophene-3-carboxamide

[0174] a) The title compound was prepared by treating2-[(aminocarbonyl)amino]-5-(1H-1-tert-butyloxycarbonylindol-2-yl)thiophene-3-carboxamidewith a mixture of 90% trifluoroacetic acid/10% water at ambienttemperature for 4 h. Evaporation gave a solid (250 mg) which was washedwith water.

[0175] MS (ES) 301 (M+H)⁺.

[0176]¹H NMR (DMSO-D6) 6.5 (s, 1H), 6.95 (m, 4H), 7.35 (m, 2H), 7.45 (d,1H), 7.6 (s, 1H), 7.62 (brs, 1H), 10.9 (s, 1H), 11.32 (brs, 1H).

[0177] b)2-[(Aminocarbonyl)amino]-5-(1H-1-tert-butyloxycarbonylindol-2-yl)thiophene-3-carboxamide

[0178] The title compound (500 mg) was prepared from1H-1-(tert-butoxycarbonyl)indol-2-yl boronic acid in a similar manner toExample 1 (d) except that the product was obtained as a solid byfiltration of the reaction mixture and was washed sequentially with 2Nsodium hydroxide solution, water and methanol.

[0179] MS (ES) 401 (M+H)⁺.

[0180]¹H NMR (DMSO-D6) 1.4 (s, 9H), 6.7 (m, 1H), 6.95 (brs, 2H), 7.2 (m,3H), 7.4 (m, 1H), 7.6 (s, 1H), 7.65 (brs, 1H), 8.0 (m, 1H), 11.04 (brs,1H).

EXAMPLE 11

[0181]3[-(Aminocarbonyl)amino]-5-(1-benzothien-3-yl)thiophene-2-carboxamide

[0182] a) 2-Bromothiophene-4-carboxylic acid

[0183] Prepared according to the method as described in J. Am. Chem.Soc., 1954, 76, 2445.

[0184] MS (ES) 205 (M−H)⁻.

[0185]¹H NMR (DMSO-D6) 7.45 (s, 1H), 8.22 (s, 1H), 12.94 (brs, 1H).

[0186] b) 2-Bromo-4-(N-t-butyloxycarbonyl)aminothiophene

[0187] 2-Bromothiophene4-carboxylic acid (3 g) was dissolved in dry warmt-butanol (24 ml). Triethylamine (2.02 ml) was added followed bydiphenylphosphoryl azide (3.12 ml). The solution was heated slowly toreflux and heating continued at reflux overnight. The reaction mixturewas then allowed to cool, poured into water (150 ml) and extracted withethyl acetate (3×100 ml). The combined extracts were dried (MgSO₄),filtered and evaporated. The crude product was purified by columnchromatography, eluting with 5% ethyl acetate in hexane, to give a whitesolid (1.69 g).

[0188] MS (ES) 276 (M−H)⁻.

[0189]¹H NMR (DMSO-D6) 1.44 (s, 9H), 7.03 (s, 1H), 7.51 (s, 1H), 9.65(s, 1H).

[0190] c) 5-Bromo-3-[(t-butyloxycarbonyl)amino]thiophene-2-carboxylicacid

[0191] 2-Bromo-4-(N-t-butyloxycarbonyl)aminothiophene (1.68 g) wasstirred in dry THF (45 ml) under argon and the solution was cooled to−78° C. Lithium diisopropylamide (7.55 ml, 2M solution) was addeddropwise and stirring continued for 3.5 h. Powdered CO₂ (excess) wasadded and the mixture stirred for a further 10 minutes before allowingto warm to room temperature. Water (50 ml) was added, the THF wasremoved in vacuo and the aqueous phase was extracted with ethyl acetate(3×40 ml). The combined extracts were washed with 1M HCl solution (50ml), water (50 ml) and brine (50 ml), dried (MgSO₄), filtered and thesolvent evaporated. The residue was triturated with dichloromethane andthe product collected by filtration as a pale yellow solid (1.57 g).

[0192] MS (ES) 320 (M−H)⁻.

[0193]¹H NMR (DMSO-D6) 9.38 (s, 1H), 7.79 (s, 1H), 1.42, (s, 9H).

[0194] d) 5-Bromo-3-(t-butyloxycarbonyl)aminothiophene-2-carboxamide

[0195] 5-Bromo-3-[(t-butyloxycarbonyl)amino]thiophene-2-carboxylic acid(0.80 g) was stirred in acetonitrile (80 ml). Hydroxybenztriazole (1.41g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.62g) were added and stirring continued at room temperature for 10 minutes.Concentrated aqueous ammonia solution (8 ml) was added and the reactionmixture was heated to reflux for 1 h. The acetonitrile was removed byevaporation. Water (100 ml) was added and the mixture was sonicated andtriturated. The resultant off-white solid was then collected byfiltration, washed with water and dried under vacuum (0.763 g).

[0196] MS (ES) 319 (M−H)⁻.

[0197]¹H NMR (DMSO-D6) 1.45 (s, 9H), 7;63 (brs, 2H), 7.78 (s, 1H), 10.40(s, 1H).

[0198] e) 3-Amino-5-bromothiophene-2-carboxamide

[0199] 5-Bromo-3-(t-butyloxycarbonyl)aminothiophene-2-carboxamide (0.76g) was stirred in dichloromethane (30 ml). Trifluoroacetic acid (51 ml)was added, the solution was stirred at room temperature for 1 h, pouredinto saturated aqueous sodium hydrogen carbonate solution (200 ml) andextracted with dichloromethane (3×100 ml). The combined extracts werewashed with brine (150 ml), dried (magnesium sulphate), filtered andevaporated to give a yellow solid (0.511 g).

[0200] MS (ES) 221 (M+H)⁺.

[0201]¹H NMR (DMSO-D6) 6.50 (brs, 2H), 6.69 (s, 1H), 6.87 (brs, 2H).

[0202] f) 3-[(Aminocarbonyl)amino-5-bromothiophene-2-carboxamide

[0203] The title compound was prepared from3-amino-5-bromothiophene-2-carboxamide in a similar manner to Example1(b).

[0204] MS (ES) 264 (M+H)⁺.

[0205]¹H NMR (DMSO-D6) 6.63 (brs, 2H), 7.41 (brs, 2H), 7.97 (s, 1H),10.02 (s, 1H).

[0206] g)3-[(Aminocarbonyl)amino-5-(1-benzothien-3-yl)thiophene-2-carboxamide

[0207] 3-[(Aminocarbonyl)amino-5-bromothiophene-2-carboxamide (0.222 g)and 1-benzothien-3-ylboronic acid (0.449 g) were sonicated in1,2-dimethoxyethane (15 ml) and saturated aqueous sodium hydrogencarbonate solution (3.5 ml) and purged with argon.Tetrakis(triphenylphosphine)-palladium (95 mg) was added and the mixturewas heated at reflux with stirring for 4.5 h, then allowed to cool andstirred at room temperature overnight. The solution was filtered andwashed through with 1,2-dimethoxyethane and water. The filtrate wasconcentrated in vacuo and taken up in dichloromethane (20 ml) andsaturated aqueous sodium hydrogen carbonate solution (20 ml). The solidproduct was collected by filtration, washed with dichloromethane, water,diethyl ether and dried (226 mg).

[0208] MS (ES) 318 (M+H)⁺.

[0209]¹H NMR (DMSO-D6) 6.60 (brs, 2H), 7.35-7.56 (m, 4H), 8.04 (s, 1H),8.10 (t, 2H), 8.25 (s, 1H), 10.08 (s, 1H).

EXAMPLE 12

[0210]2-[(Aminocarbonyl)amino]-5-(2-morpholin-4-ylmethylbenzo[b]thiophen-5-yl)thiophene-3-carboxamide

[0211] 4-(5-Bromobenzo[b]thiophen-2-ylmethyl)morpholine (Beilstein Reg.No. 1115497) (230 mg) in dry THF was treated with triisopropyl borate(291 mg) and was cooled under argon to <−70° C. with stirring. Afterdropwise addition of n-butyl lithium (0.921 ml, 1.6M in hexanes) thereaction was allowed to warm to room temperature. The solvent wasevaporated and replaced with a mixture of dimethoxyethane (20 ml) andsaturated aqueous sodium hydrogen carbonate (9 ml). To this mixture wasadded under argon 2-[(aminocarbonyl)amino]-5-bromothiophen-3-carboxamide(98 mg) and tetrakis-triphenyl phosphine palladium (0) (25 mg) and thereaction heated to 90° C. for 1.5 h. The reaction mixture was evaporatedto remove the bulk of the organics and the residue distributed between2M aqueous sodium hydroxide (30 ml) and dichloromethane. Afterfiltering, the organic phase was separated and extracted with a fuithervolume of sodium hydroxide solution (10 ml). The combined aqueousextracts were acidified to pH 8 and filtered. After drying the solid wastriturated with diethyl ether and dried to give a powder (27 mg).

[0212] LCMS 417 (M+H)⁺.

[0213]¹H NMR (DMSO-D6) 2.47 (m, 4H), 3.65 (m, 4H), 3.80 (s, 2H), 6.95(brs, 2H), 7.3 (brs, 1H), 7.33 (s, 1H), 7.5 (m, 1H), 7.69 (brs, 1H),7.75 (s, 1H), 7.91 (m, 2H), 11.0 (s, 1H).

EXAMPLE 13

[0214]2-[(Aminocarbonyl)amino]-5-[4-(2-morpholin-4-ylethoxy)-1-benzothien-2-yl]-3-thiophenecarboxamide

[0215] a) The title compound was prepared from4-[2-(1-benzothien-4-yloxy)ethyl]morpholine in a similar manner toExample 12, except that the reaction mixture was heated at 90° C. for 4h. After removing the solvent in vacuo, the residue was treated with 3Msodium carbonate/dichloromethane and the solid filtered from theinterface. Purification by preparative hplc gave the product.

[0216] MS (ES) 447 (M+H)⁺.

[0217]¹HNMR (DMSO-D6) 2.5 (m, 4H), 2.8 (t, 2H), 3.55 (m, 4H), 4.25 (t,2H), 7.0 (m, 3H), 7.15 (m, 2H), 7.35 (m, 3H), 7.8 (m, 1H), 11.05 (brs,1H).

[0218] b) 4-[2-[(1-Benzothien-4-yloxy)ethyl]morpholine

[0219] 4-(2-Chloroethyl)morpholine hydrochloride (0.74 g),1-benzothiophene-4-ol (0.5 g) and potassium carbonate (1.1 g) indimethylformamide (15 ml) were heated and stirred at 80° C. for 6 h.After cooling, the mixture was poured into water and extracted twicewith ethyl acetate. The combined solvent phase was washed twice withbrine, dried (magnesium sulphate) and evaporated to give the product(0.7 g).

[0220] MS (ES) 264 (M+H)⁺.

[0221]¹H NMR (DMSO-D6) 2.5 (m, 4H), 2.8 (t, 2H), 3.55 (m, 4H), 4.25 (t,2H), 6.9 (d, 1H), 7.25 (t, 1H), 7.4 (d, 1H), 7.55 (d, 1H), 7.6 (d, 1H).

[0222] c) 1-Benzothiophene-4-ol

[0223] The compound was prepared as described in J.Amer.Chem.Soc., 1955,77, 5939.

EXAMPLE 14

[0224]2-[(Aminocarbonyl)amino]-5-{2-[4-methylphenylsulphonyl]-1.2,3,4-tetrahydroisoquinolin-6-yl}thiophene-3-carboxamide

[0225] a) The title compound was prepared from6-bromo-2-[4-methylphenylsulphonyl]-1,2,3,4-tetrahydroisoquinoline in asimilar manner to Example 13, except that the reaction mixture washeated at 80° C. for 18 h. After removing the solvent in vacuo, theresidue was treated with 2M sodium hydroxide and dichloromethane and theseparated aqueous phase was adjusted to pH 8 using 36% hydrochloricacid. The crude product was purified by preparative hplc.

[0226] MS (ES) 471 (M+H)⁺.

[0227]¹H NMR (DMSO-D6) 2.4 (s, 3H), 2.8 (m, 2H), 3.2 (m, 2H), 4.1 (s,2H), 6.9 (br, 2H), 7.15 (m, 1H), 7.3 (m, 1H),7.4 (m, 2H),7.5 (m, 1H),7.7-7.9 (m, 5H), 11.0 (s, 1H).

[0228] b)6-Bromo-2-[4-methylphenylsulphonyl]-1,2,3,4-tetrahydroisoquinoline

[0229] 2-[3-Bromophenyl]-N-(4-methylphenylsulphonyl)ethylamine (7.44 g)was stirred in chloroform (100 ml) under argon at 5° C. during thesequential addition of 37-40% formaldehyde (3.5 ml) and phosphorusoxychloride (30 ml). The mixture was then refluxed for 3 h, cooled,poured into dichloromethane (250 ml)/saturated sodium bicarbonate (300ml) and solid sodium bicarbonate (160 g) cautiously added in portions at5° C. The aqueous phase was further extracted with dichloromethane andthe combined organic phases washed with saturated sodium bicarbonate andwater, dried (MgSO₄) and evaporated to give an oil, which crystallisedfrom isohexane/toluene to give the product (3.48 g).

[0230] MS (ES) 365 (M)⁺.

[0231]¹H NMR (CDCl₃) 2.43 (s, 3H), 2.89 (t, 2H), 3.34 (t, 2H), 4.18 (s,2H), 6.89 (d, 1H), 7.23-7.30 (m, 2H obscured), 7.33 (d, 2H), 7.72 (d,2H).

[0232] c) 2-[3-Bromophenyl]-N-(4-methylphenylsulphonyl)ethylamine

[0233] 3-Bromophenylethylamine hydrochloride (9.44 g) was added to THF(60 ml) containing triethylamine (12.24 ml) and stirred-under argon at5° C. during the portionwise addition over 15 minutes of4-methylphenylsulphonyl chloride (11.44 g). The slurry was diluted withTHF (50 ml) and stirred for 16 h. The solid was filtered off, washedwith THF and the filtrate evaporated. The residue was dissolved in ethylacetate, washed with 1N hydrochloric acid, water, brine and dried(MgSO₄). Chromatography on flash silica, eluting with 0 to 25% ethylacetate in isohexane gave the product (9.67 g).

[0234] MS (ES) 352 (M−H)⁻.

[0235]¹H NMR (CDCl₃) 2.44 (s, 3H), 2.74 (t, 2H), 3.23 (q, 2H), 4.36 (t,1H), 7.03 (d, 1H), 7.14 (t, 1H), 7.17 (m, 1H), 7.30 (d, 2H), 7.35 (dd,1H), 7.69 (dd, 2H).

[0236] d) 3-Bromophenylethylamine Hydrochloride

[0237] The free base of the title compound has CAS Registry Number58971-11-2 and Beilstein Registry Number 2716071.

EXAMPLE 15

[0238]3-[(Aminocarbonyl)amino]-5-(1-benzothien-2-yl)thiophene-2-carboxamide

[0239] The title compound was prepared from3-[(aminocarbonyl)amino-5-bromothiophene-2-carboxamide and1-benzothien-2-ylboronic acid in a similar manner to Example 11 (g).

[0240] MS (ES) 318 (M+H)⁺.

[0241]¹H NMR (DMSO-D6) 6.64 (brs, 2H), 7.33-7.47(m, 2H), 7.49 (brs, 2H),7.71 (s, 1H), 7.80-7.90 (m, 1H), 7.90-8.02 (m, 1H), 8.23 (s, 1H), 10.05(s, 1H).

Pharmacological Evaluation of Compounds

[0242] IKK2 Filter Kinase Assay

[0243] Compounds were tested for inhibition of IKK2 using a filterkinase assay. The test compounds were dissolved to 10 mM indimethylsulphoxide (DMSO). The compounds were then diluted 1 in 40 inkinase buffer (50 mM Tris, pH 7.4 containing 0.1 mM EGTA, 0.1 mM sodiumorthovanadate and 0.1% β-mercaptoethanol). 1 in 3 serial dilutions weremade from this solution with 2.5% DMSO in kinase buffer. 20 μl ofcompound dilution was added to wells of a 96 well plate in duplicate. 20μl 2.5% DMSO in kinase buffer instead of compound was added to controlwells (0% inhibition). 20 μl 0.5 M EDTA was added instead of compound tobackground wells (100% inhibition).

[0244] 10 μl of a mixture of magnesium acetate, unlabelled ATP, and³³P-labelled ATP was added to each well made such that the finalconcentration was 10 mM magnesium acetate, 1 μM ATP and 0.1 μCi ³³P ATP.20 μl of a mixture of IKK2 (0.15 μg/well), 1-53 GST-IκB (0.5 μg/well)and bovine serum albumin (BSA) (8.5 μg/well) was added to each well tostart the reaction. The final reaction volume was 50 μl.

[0245] The kinase reactions were incubated at 21° C. for 80 minutes andthe reaction stopped by precipitating the protein by the addition of anequal volume (50 μl) of 20% trichloroacetic acid (TCA). The precipitatewas allowed to form for 10 minutes and then filtered onto a GF/Cunifilter 96 well plate. Each filter was washed twice with approximately1 ml 2% TCA. The filter plate was dried at 30-40° C. for 60 minutes, 20μl scintillant was added to each well and the plate sealed andradioactivity counted on a Packard Topcount microplate scintillationcounter.

[0246] When tested in the above assay, the compounds of Examples 1 to 15gave IC₅₀ values of less than 10 μM indicating that they are expected toshow useful therapeutic activity.

[0247] IKK1 Filter Kinase Assay

[0248] The selectivity of compounds was assessed by testing them forinhibition of IKK1 using a filter kinase assay. The assay conditionswere identical to the IKK2 filter kinase assay except that a mixture ofIKK1 (0.25 μg/well) and 1-53 GST IκB (9 μg/well) was added to each wellto start the reaction.

[0249] Inhibition of LPS-Induced TNFα Production by PBMCs

[0250] The effect of test compounds on nuclear factor kappa B (NFκB)activation in cells was assessed by measuring inhibition of tumournecrosis factor alpha (TNFα) production by human peripheral bloodmononuclear cells (PBMCs) stimulated by bacterial lipopolysaccharide(LPS).

[0251] Human blood (250 ml), anticoagulated with heparin, was collectedfrom healthy volunteers. Aliquots of blood (25 ml) were layered on 20 mlLymphoprep (Nycomed) in 50 ml polypropylene centrifuge tubes. The tubeswere centrifuged (Sorval RT600B) at 2,500 rpm for 30 minutes. The cloudylayer containing PBMCs was collected with a fine tipped Pasteur pipette,transferred into 8 clean polypropylene centrifuge tubes (approximately10 ml per tube) and diluted to 50 ml with phosphate-buffered saline(PBS). These tubes were centrifuged at 2,000 rpm for 8 minutes. PBS (10ml) was added to each cell pellet and the cells were gentlyre-suspended. The cells were pooled in 4 centrifuge tubes, PBS was addedto each tube to make the volume up to 50 ml and the tubes werecentrifuged at 1,400 rpm for 8 minutes. The cell pellets were againre-suspended in 10 ml PBS, pooled in 2 centrifuge tubes, the volume madeup to 50 ml with PBS and the tubes centrifuged at 900 rpm for 10minutes.

[0252] The final cell pellets were gently re-suspended in 10 ml tissueculture medium (RPMI containing 1% heat-inactivated human serum,L-glutamine and penicillin and streptomycin), combined into 1 tube andthe volume made up to 30 ml with RPMI medium. The cells were counted andthe cell suspension was diluted to 2.6×10⁶ cells/ml.

[0253] Test compounds were dissolved in DMSO to 10 mM and diluted 1 in250 (40 μM) with RPMI medium. The compounds were then serially diluted 1in 3 with 0.4% DMSO in RPMI medium. Aliquots of test compound dilutions(50 μl) were transferred to the wells of a 96-well plate. Control wellscontained 0.4% DMSO in RPMI instead of compound.

[0254] Aliquots of the cell suspension (100 μl) were added to each welland the plates incubated at 37° C. for 30 minutes. 50 μl of 40 μg/ml LPS(Sigma, L-4130) was added to wells to stimulate TNFα production by thecells and the plates were incubated overnight at 37° C. RPMI medium (50μl) was added to negative control wells instead of LPS. The finalincubation volume was 200 μl.

[0255] Plates were centrifuged for 4 minutes at 1,200 rpm andsupernatants were removed for measurement of TNFα concentration.Viability of the remaining cell pellet was measured using WST-1 reagent(Boehringer Mannheim, 1044807). 100 μl RPMI medium containing 10 μlWST-1 reagent was added to each well and the plates were incubated for0.5 to 3 h. The absorbance at 450 nm was then measured using a 96-wellplate spectrophotometer.

[0256] TNFα in the supernatants (freshly harvested or stored frozen at−20° C.) were measured using an enzyme-linked immmunosorbant assay(ELISA). The ELISA plate was prepared by coating the wells of a 96 wellplate with a sheep anti-human TNFα monoclonal antibody (100 μl of 1μg/ml antibody diluted in coating buffer; 0.5 M carbonate/bicarbonatebuffer, pH 9.6 containing 0.2 g/l sodium azide) and incubating overnightat 4° C. Blank wells were not coated. The wells were washed once with0.1% BSA in PBS containing 0.05% Tween (PBS/Tween) then incubated for 1h at room temperature with 1% BSA in coating buffer (200 μl). The wellswere then washed 3 times with 0.1% BSA in PBS/Tween.

[0257] The samples of supernatant from the PBMC incubation were diluted1 in 3 with 1% BSA iii PBS/Tween. 100 μl aliquots of these dilutionswere added to the ELISA plate. Other wells contained 100 μl TNFαstandard (10, 3.3, 1.1, 0.37, 0.12, 0.04, 0.014 and 0 ng/ml). The ELISAplate was incubated at room temperature for 2 h before the wells werewashed 3 times with 0% BSA in PBS/Tween. A rabbit anti-human TNFaantibody (100 μl of a 2.5 μg/ml solution) was added to each well and theplate incubated at room temperature for 1.5 h. The wells were thenwashed 3 times with 0.1% BSA in PBS/Tween. Goat anti-rabbit IgG-horseradish peroxidase conjugate (ICN, 674371; 100 μl of a 1 in 10,000dilution) was added to each well and the plate incubated at roomtemperature for 1.5 h. The wells were washed 3 times with 0.1% BSA inPBS/Tween.

[0258] Peroxidase substrate was prepared by dissolving a 1 mg TMB tablet(Sigma, T-5525) in 100 μl DMSO (100 μl) and adding this and 36 μl UHPO(BDH, 30559; 1 g tablet dissolved in 25 ml distilled water) to 10 ml0.1M citrate/acetate buffer, pH6. 100 μl substrate was added to eachwell and the plate incubated in the dark at room temperature forapproximately 30 minutes. The reaction was stopped by adding 25 μl 2 Msulphuric acid to each well. The absorbance at 450 nm was measured in a96 well plate spectrophotometer.

1. A compound of formula (I)

in which: R¹ represents NH₂ or R¹ represents a methyl group optionallysubstituted by one or more groups selected independently from C₁-C₄alkyl, C₃-C₆ cycloalkyl, halogen, hydroxyl, C₁-C₄ alkoxy, S(O)_(v)CH₃and NR⁴R⁵; X represents O or S; R² represents hydrogen, halogen, cyano,nitro, —NR⁶R⁷, —CONR⁶R⁷, —COOR⁶—NR⁶ COR⁷, —S(O)_(m)R⁶, —SO₂NR⁶R⁷, —NR⁶SO₂ R⁷, C₁-C₂ alkyl, trifluoromethyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl,trifluoromethoxy, C₁-C₂ alkoxy or C₁-C₂ alkanoyl; A represents a fusedbicyclic ring system wherein one ring is a phenyl ring or a 5- to7-membered heteroaromatic ring containing one to three heteroatomsselected independently from O, N and S; and the other ring is either afused phenyl ring or a fused 5- to 7-membered heteroaromatic ringcontaining one to three heteroatoms selected independently from O, N andS; or a fused 5- to 7-membered saturated ring optionally incorporatingone to three heteroatoms selected independently from oxygen, nitrogenand sulphur; said fused bicyclic ring system being optionallysubstituted by one or more substituents selected independently fromhalogen, cyano, nitro, —NR⁸ COR⁹, —S(O)_(S)R⁸, —SO₂NR⁸R⁹, —NR⁸ SO₂R⁹ andC₁-C₆ alkyl; n represents an integer 0, 1 or 2; and when n represents 2,each R³ group may be selected independently; R³ represents a group—W—Y—Z wherein: W represents O, S(O)_(r), NR¹³, CH₂, —CH₂—O— or a bond;Y represents a bond or Y represents a group —(CH₂)_(p)—X—(CH₂)_(q)—wherein p and q independently represent an integer 0, 1 or 2; and Xrepresents O, —CO— or CR¹⁴R¹⁵ R¹⁴ and R¹⁵ independently represent H, CH₃or F; or R¹⁴ represents H or CH₃ and R¹⁵ represents hydroxyl or OCH₃; orthe group CR¹⁴R¹⁵ together represents a C₃-C₆ cycloalkyl ring; Zrepresents: (a) a phenyl ring or a 5- or 6-membered heteroaromatic ringcontaining one to three heteroatoms selected independently from O, N andS; said phenyl or heteroaromatic ring being optionally substituted byone or more substituents selected independently from halogen, cyano,—NR¹⁶R¹⁷, —CONR¹⁶R¹⁷, —COOR¹⁶, —COR¹⁶—NR¹⁶COR¹⁷, —S(O)_(u)R¹⁶,—SO₂NR¹⁶R¹⁶—NR¹⁶SO₂R¹⁷, hydroxyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkyl and C₁-C₆ alkoxy; said alkyl or alkoxy group being optionallyfurther substituted by one or more groups selected from halogen, cyano,hydroxyl, C₁-C₄ alkoxy and NR¹⁸R¹⁹; or (b) a saturated 3- to 7-memberedring optionally incorporating one or two heteroatoms selectedindependently from O, N and S, and optionally incorporating a carbonylgroup; said saturated ring being optionally substituted by one or moresubstituents selected independently from halogen, cyano, —NR¹⁶R¹⁷,—CONR¹⁶R¹⁷, —COOR¹⁶, —COR¹⁶, —NR¹⁶ COR¹⁷, —S(O)_(u)R¹⁶—SO₂NR¹⁶R¹⁷,—NR¹⁶SO₂R¹⁷, hydroxyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkyl andC₁-C₆ alkoxy; said alkyl or alkoxy group being optionally furthersubstituted by one or more groups selected from halogen, cyano,hydroxyl, C₁-C₄ alkoxy and NR¹⁸ R¹⁹; or (c) Z represents hydroxyl, C₁-C₆alkoxy, CF₃, CHF₂, CH₂F or NR²⁰R²¹ where R²⁰ and R²¹ are independentlyhydrogen or C₁-C₆ alkyl optionally substituted by C₁-C₄ alkoxy; R⁴ andR⁵ independently represent H or C₁-C₄ alkyl; or the group NR⁴R⁵represents a 5- or 6-membered saturated azacyclic ring optionallycontaining a further O, S or NR²³ group; where R²³ is hydrogen or C₁-C₄alkyl; R⁶ and R⁷ independently represent H or C₁-C₂ alkyl; R⁸ and R⁹independently represent H or C₁-C₆ alkyl; R¹³ represents H or C₁-C₄alkyl; R¹⁶ and R¹⁷ independently represent H or C₁-C₆ alkyl; or thegroup NR¹⁶R¹⁷ represents a 5- or 6-membered saturated azacyclic ringoptionally containing a further O, S or NR²⁴ group; where R²⁴ ishydrogen or C₁-C₆ alkyl; R¹⁸ and R¹⁹ independently represent H or C₁-C₄alkyl; or the group NR¹⁸R¹⁹ represents a 5- or 6-membered saturatedazacyclic ring optionally containing a further O, S or NR²⁵ group; whereR²⁵ is hydrogen or C₁-C₄ alkyl; m, r, s, u and v independently representan integer 0, 1 or 2; and pharmaceutically acceptable salts thereof. 2.A compound of formula (I), according to claim 1, wherein X representsoxygen.
 3. A compound of formula (I), according to claim 1, wherein R¹represents NH₂.
 4. A compound of formula (I), according to claim 1, inwhich R² represents H or methyl.
 5. A compound of formula (I), accordingto claim 1, selected from:2-[(aminocarbonyl)amino]-5-(2-benzofuranyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-5-(3-quinolinyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-5-(8-quinolinyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-5-(2-benzothiophenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-5-(3-benzothiophenyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-5-(5-indolyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(1,4-benzodioxan-6-yl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(3-indolyl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-4-methyl-5-(1,3-benzodioxo-5-yl)-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-5-(1H-indol-2-yl)thiophene-3-carboxamide;3-[(aminocarbonyl)amino]-5-(1-benzothien-3-yl)thiophene-2-carboxamide;2-[(aminocarbonyl)amino]-5-(2-morpholin-4-ylmethylbenzo[b]thiophen-5-yl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-[4-(2-morpholin-4-ylethoxy)-1-benzothien-2-yl]-3-thiophenecarboxamide;2-[(aminocarbonyl)amino]-5-{2-[4-methylphenylsulphonyl]-1,2,3,4-tetrahydroisoquinolin-6-yl} thiophene-3-carboxamide;3-[(aminocarbonyl)amino]-5-(1-benzothien-2-yl)thiophene-2-carboxamide;and pharmaceutically acceptable salts thereof.
 6. A process for thepreparation of a compound of formula (I), according to claim 1, whichcomprises: (a) reaction of a compound of formula (II):

wherein A, R², R³ and n are as defined in claim 1 with an isocyanate oran isothiocyanate or an acyl derivative, R¹—CO—L, where L is a leavinggroup; or (b) reaction of compound of formula (III)

wherein R³, n and A are as defined in claim 1 with a compound of formula(IV)

wherein X, R¹ and R² are as defined in claim 1 and LG represents aleaving group; or (c) reaction of compound of formula (V)

wherein R³, n and A are as defined in claim 1 and LG represents aleaving group, with a compound of formula (VI)

wherein X, R¹ and R² are as defined in claim 1; and where necessaryconverting the resultant compound of formula (I), or another saltthereof, into a pharmaceutically acceptable salt thereof; or convertingthe resultant compound of formula (I) into a further compound of formula(I); and where desired converting the resultant compound of formula (I)into an optical isomer thereof.
 7. A pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt thereof, as claimed in claim 1 in association with apharmaceutically acceptable adjuvant, diluent or carrier.
 8. A processfor the preparation of a pharmaceutical composition as claimed in claim7 which comprises mixing a compound of formula (I), or apharmaceutically acceptable salt thereof, as claimed claim 1 with apharmaceutically acceptable adjuvant, diluent or carrier. 9-10(Cancelled).
 11. A method of treatment or prophylaxis of a patienthaving an inflammatory disease, the method comprising: using a compoundof formula (I), or a pharmaceutically acceptable salt thereof, asclaimed in claim 1 in the treatment or prophylaxis of the inflammatorydisease.
 12. The method as claimed in claim 11 wherein the inflammatorydisease is asthma.
 13. The method as claimed in claim 11 wherein theinflammatory disease is rheumatoid arthritis.
 14. The method as claimedin claim 11 wherein the inflammatory disease is multiple sclerosis. 15.The method as claimed in claim 11 wherein the disease is chronicobstructive pulmonary disease.
 16. The method as claimed in claim 11wherein the disease is cancer.
 17. A method of treating, or reducing therisk of, diseases or conditions in which inhibition of IKK2 activity isbeneficial which comprises administering to a person suffering from orat risk of said disease or condition a therapeutically effective amountof a compound of formula (I), or a pharmaceutically acceptable saltthereof, as claimed in claim 1.